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In this final part of my series on antibiotic resistance, I want to discuss the use of antimicrobials in the food supply. If you need to review other areas of antibiotic resistance, check out “Discussing the Disappearing Miracle” (a lesson in what antibiotic resistance is and is not), “Quitting When You’re Not Really Ahead“ (how people accidentally contribute to antibiotic resistance), and “No, the Z-Pack Won’t Treat The Flu” (how overprescription of antibiotics contributes to resistance). In this article, I’ll focus on how antibiotics are used in the growth of animals destined for consumption, what that does in terms of producing resistance, and what we can do in response.

I know the article is called “SuperChickens?”, but I actually want to start by talking turkey. If you live in the United States, you’ve likely seen the president pardoning a turkey on Thanksgiving Day. This is an old tradition – you can see below a photograph of Kennedy pardoning a turkey next to a similar photo of Obama doing the same thing 50 years later (1). What’s remarkable in this photo is the difference in the two birds. Kennedy’s turkey is much closer in size to wild turkeys (2), which usually weigh between 7.6 kg (toms) and 4.26 kg (hens), maxing out at 16.85kg (3). In comparison, the turkeys that grace most tables average 13.5 kg, maxing out at 39 kg (4). Wild turkeys are half the mass of modern, domesticated turkeys (2). Nor did that change happen by accident.

Until the 1950s, most turkeys were similar to the wild birds. However, with the arrival of antibiotics, the average size of the bird began to change. While this was initially done through selective breeding, the demand for meat incentivized not only breeding for size, but also speed from egg to adult. The demand for a bigger bird faster drove competition. When it was discovered that antibiotic use increased the growth rate of chicks in 1948 (chicks given antibiotics grew larger, faster, than those not given antimicrobials), it helped create a new market for the new drugs (5). Since faster growth resulting in bigger birds was the desired outcome, the animals’ feed was soon supplemented with antibiotics.

I know what you’re wondering – who even thought that feeding antibiotics to chickens was a good or necessary idea? It turns out that the introduction of antibiotics was an accident. Researchers were studying other ways to supplement growth, focusing on vitamin B12 (which includes cobalt, a trace metal important for red blood cell development, neurological function, and DNA synthesis) (6). The researchers were looking for different sources of B12, and one easily available source used was the cellular remains of Streptomyces auerofaciens (5). These bacteria were used to develop the tetracycline antibiotic aureomycin, and the cellular remains were what was left when the antibiotics were extracted from the bacteria. They used it because it was an amazing source of the vitamin for a very low cost – it was waste from another process already being done. Another source of B12 was beef liver. Researchers discovered that the chicks given bacterial remains grew 24% faster than the chicks given liver. While it wasn’t initially clear that the antibiotic residue in the cellular remains caused the growth, the vitamin was eventually ruled out as the cause of improved growth (5).

Suddenly, agriculture had an easy way to improve their product – they could grow animals faster, larger, which meant they could use less feed – the sooner an animal was an adult, the sooner it could be sent to market. Since the initial doses of antibiotics were accidental and very low, antibiotics for growth promotion also use very low doses. As a result, the bacterial population in animals are exposed to the drugs used to treat an infection in a sick animal, but over the entire course of their life. This establishes an excellent environment for the bacteria to adapt to the drug and become resistant to it.

See, resistance occurs when a bacteria is exposed to a drug, but not all of the bacteria are killed by the drug. The weakest bacteria die off, leaving those not actually susceptible. During clinical dosing of antibiotics (when used to treat an infection), high doses are used over a short course. This makes it more difficult for the bacteria to adapt. The high dose is more likely to eliminate more of the bacteria, and the short course, or amount of time involved actually taking the medication, means that any resistant bacteria don’t remain exposed to the drug long-term. That gives our rapidly multiplying bacterial population no opportunity to select for resistance. Instead, as the resistant bugs die off, random chance re-enters the evolutionary picture – there’s nothing present to make the resistant bugs more likely to survive and reproduce, so there’s no benefit to resistance.

But when the exposure is low, more of the bacteria survive, giving a larger population the ability to adapt (versus the much smaller population of resistant bacteria that exist after the rest are killed off). What makes this worse is when that exposure occurs over a long period of time. The benefit of remaining resistant continues, which ensures that the larger population is more likely to retain resistance. Random chance is thus limited when mutations occur – the pressure to remain resistant persists within the bacterial community, producing more resistant bacteria in greater numbers.

Growth promotion isn’t the only use for antibiotics in agriculture. When one or more animals is ill, or when stress is high within the population (such as weaning the young or transporting them), farmers use antibiotics to prevent illness in the entire community. This preventative use makes use of higher doses than those used for growth promotion, but still lower than needed to treat active infection. This subclinical dosing (lower than needed to treat an infection) in both cases increases the exposure of bacteria to the same drugs used to treat disease in both animals and humans. While this preventative use need not be used over an extended period time, not all farms as judicious as they could be in their use. However, this use of antibiotics creates a similar selection pressure on the bacterial populations within the animal – it’s still high enough to eliminate the most susceptible bacteria, but because no active infection is present, the animals’ immune system never activates to eliminate the remaining, resistant population. Worse, because this dose is higher than the one used for growth promotion, the percentage of the population that remains is made up of mostly resistant bacteria (as opposed to resistant and non-susceptible bacteria that remain with the very low doses involved in growth promotion).

The least controversial use of antibiotics in food production occurs when an animal is actually ill. In these cases, sick animals are given clinical doses of antibiotics, just as the rest of us are. Since the animal is reliant on another to dose them, either in feed, water, or via injection, the risk of forgetting a dose is reduced. Some farmers do this by adding the medication to the water supply, but if it is only supplied to the infected animals, the risk of resistance drops. Since it’s illegal (and unprofitable) to sell sick animals, very few object to clinical uses in these settings (although some farms ban the use of all antibiotics, or won’t sell animals that required treatment).

OK, so animals can develop resistant bacteria just like people do. You may be asking yourself why that matters. We can’t give animals cold medicine when they get sick – surely we’re not using “people” medicine for animals, right? Wrong. In fact, farmers are more likely to use the inexpensive generic drugs that are less beneficial for human use due to increased resistance. This might not seem like a problem – if we can’t use them anyway, why not get some benefit? Sadly, some of these old medications are held in reserve to treat bacterial infections that are resistant to almost all antibiotics, but that were never exposed to these older drugs. As a result, using these “last line” drugs can create bacteria that are not only resistant to the drugs commonly used to treat infections, but also to these older drugs (7,8).

You’re wondering how, if sick animals can’t be sold, resistant bacteria transfer from healthy animals to people. There are a few ways, but nearly all of them are tied to food safety practices. The possibly grossest method is via feces: the animal passes stool, and water washes the resistant bacteria into a water source. This contaminated water is then used to water fresh vegetables that are likely not cooked before consumption. In fact, this is exactly how the Escherichia coli outbreak in 2006 occurred. A cattle farmer leased land to a spinach farmer, which became contaminated by infected cattle feces in the water supply. Because spinach is often consumed raw, the bacteria were able to reproduce without adequate control and without being eliminated when the food was cooked.

That last point – that the food wasn’t cooked – is the key to most of the remaining transferrals. Contaminated raw meats can spread bacteria to people as well. Meat that isn’t cooked to a temperature that kills the bacteria can lead to consumption of viable bacteria. This is why menus note that eating meat or eggs can cause problems in certain groups – undercooked eggs are another possible source of viable bacteria. But even if you’re careful to always cook your food to the right temperature, if you don’t cool it correctly and keep it out of the danger zone (4° – 60° Celsius), the bacteria can grow to a dangerous population after cooking. More than that, putting hot food into the refrigerator or freezer can raise the temperature of surrounding foods (including those that are pre-cooked) long enough to allow bacterial growth.

“Oh,” you say, “but I’m always careful to have my meat well done, my eggs over-hard, and to put leftovers away immediately without letting them heat surrounding food.” That’s awesome, but you’re not out of danger yet. There’s still cross-contamination to consider. This can occur if you cut or handle raw meat with the same hands or tools that you then use to handle fresh, uncooked food. This is why cutting boards for designated purposes have increased in popularity – keeping your raw chicken on one board, your red meat on another, your fruit and veg on yet another, helps reduce the risk of putting fruits and veggies into a pool left behind by raw meat. But if you don’t change your knife or wash your hands, you may still have cross contamination issues.

Cross-contamination can even occur before you bring your food home. If your meat and your fresh food aren’t stored correctly, the meat may contaminate the fresh food in your supermarket buggy or in your refrigerator. Meat stored above a crisper drawer may leak into the crisper drawer, especially if it isn’t wrapped well. Food put into the fridge without cleaning where the raw meat had been can then be infected as well. It’s also possible that food handlers (before it ever reached you) could be the cause of cross contamination.

Once you’ve consumed the contaminated food, the bacteria have the perfect host in which to grow and reproduce. As they grow, they interact with other bacteria in your body (remember the lesson in “Discussing the Disappearing Miracle”). The plasmids that contain the genes for resistance are then shared with bacteria present in your body, and now those bacteria are resistant to the drugs coming from the animal population.

Many have suggested that this sort of cross contamination between agricultural and human bacteria is incredibly unlikely. Sadly, a recent study in China (7,8) illustrates that resistant bacteria in animals are present in food and have caused disease in humans. Worse, the drug resistance is to a drug-of-last-resort. Colistin is an old antibiotic (developed in 1959), meaning it is now available in a generic formulation and thus cheap. It was also not widely used in humans due to the tendency to cause kidney problems, limiting the ability of bacteria common to humans to develop resistance to it. Because it is cheap, colistin has been widely used in agriculture, particularly in Asia, where it makes up 73.1% of colistin production. However, because so few things have had opportunity to develop resistance, infections that are resistant to other treatments are treated with colistin (when your choices are maybe develop kidney problems or die of the bacterial infection, medical professionals tend to opt for risking the kidney problems over death).

The study in China found colistin resistant bacteria in animals, raw meat in stores, and in 1% of hospital treated infections. Worse, this resistance has already spread from China and is now present in Malaysia. This means that patients are already seriously ill from antibiotic resistant infections that are also resistant to our last defense (7). We’re already seeing the first waves of a time when antibiotics may no longer be available. And while 1% may not seem alarming, remember that resistance spreads fast because bacteria share.

At the start of this article, I suggested that I would include information on how you, as an ordinary person, can help fight antibiotic resistance from agricultural use. I’ve already told you that safe food handling can help prevent the spread of bacteria to you and those you love, but that’s only one way to fight this growing threat. Many companies are already taking the steps necessary – Denmark (9) has outlawed the use of antibiotics in animals destined for market, and two turkey producers (10) have outlawed them either entirely or for subclinical usage. You can help make it more profitable for companies to take the longer road to growth by buying from trusted brands or demanding that your favorite brands eliminate subclinical use. You can demand better living conditions for animals bred for market – I didn’t even discuss how the terrible living conditions trigger preventative use of antibiotics or lead to sicker animals. The eggs that came from free-range hens are far less likely to have had antibiotics, because those hens are less likely to need them. But free-range hens require more land and more time and more food to grow, which increases the cost to the producer and the consumer.

Antibiotic resistance didn’t happen overnight. Many smart people are working on how to solve it, to keep our miracle intact for generations to come. Fixing a problem this big isn’t going to be easy or cheap. But you can help. You can demand that your food be antibiotic free, you can insist on only taking antibiotics when they’re actually necessary, and you can take every pill on time, to the end, even when you feel better (by the way, that’s actually a decent test to determine if your infection is viral or bacterial: viral infections last 7-10 days before the immune system can wipe them out. Bacterial infections treated by antibiotics will improve in a day or two. So if your doctors writes you a script for antibiotics, and you take them, and you aren’t better in a day or two, odds are your infection wasn’t bacterial. I give you permission to remind your doctor about the risks of antibiotic resistance). You can also educate others, like I did here. Understand the risks, do the hard work to help reduce them, and encourage others to do the same. Together, we might just be able to win.

NB: I included not only the sources I cited here, but also several that I used as I prepared this article. Watch for a video from “In A Nutshell” to explain this very topic, as well. It isn’t cited here, but it’s coming.

In my last post, I introduced the problem of antibiotic resistance. It’s important to note that resistance is something developed over time – some bacteria were never susceptible to certain antibiotics in the first place. For instance, if I’m one of the three little pigs, and I build my house out of bricks, all the huffing and puffing of one wolf isn’t really going to make much difference. Neither will fire. But if I’d built it out of logs, I might be safe from the wolf’s breath, but not from flames. Susceptibility is about what drugs can be effectively used against a pathogen, or cause of disease. Resistance is about the ability of a pathogen to lose susceptibility to a drug that was previously effective. If it never worked, the pathogen isn’t resistant.

That’s an important distinction because bacteria, when they share, can share resistance factors (plasmids) for antibiotics without any consideration for their own susceptibility. Jim, the reeking Escherichia, can pick up a plasmid for resistance to penicillin. It does Jim no good – Jim was never susceptible in the first place. The mechanisms that penicillin uses to attack bacteria, the specific protein structures that penicillin targets, aren’t present on Jim. Penicillin can’t target what isn’t present. But Jim can still take the plasmid, tuck it away, and share freely. Jim shares resistance that he doesn’t need – which, as I said before, is an enormous problem. I also said there was a bigger problem – you and I helping the bacteria.

Your doctor prescribes antibiotics. Now, there’s times when they’re needed and times when they aren’t (See “No the Z-Pack won’t treat the Flu”, and “SuperChickens?” for the latter), but we’re going to ignore those occasions. We’ll assume that your doctor is well educated on the dangers of antibiotic resistance and not only knows when to prescribe antibiotics and when not to, but even knows how to choose which antibiotic to prescribe. So the doctor sends you off to the pharmacy with your prescription and very clear instructions: “Take every pill, on time, as directed, even when you start to feel better, and finish this prescription!” You get to the pharmacy, where the pharmacist hands you your prescription and tells you, very sternly, “Take every single pill, on time, as directed, even when you start to feel better, and finish this prescription!” You shake your head and go on your way, doubtful that you’ll ever feel better.

What they don’t tell you, or maybe they do, but you don’t hear, because you’re all very busy people, is why you have to take every single pill on time and finish the prescription, as directed, even after you start to feel better. They don’t tell you about what the antibiotics do to the bacteria inside your body, or what the bacteria do in response. So you start taking them, because anything would be better than how you feel now. Every hour, though, you start to recover, and it doesn’t take more than a few days, maybe even just 2, before you’re having trouble remembering those pills. Especially if they’re big. Or you have to take them two or three times a day. Or both. Oh yeah, I know how it is. I’ve been there. And you forget. And you start feeling better. And you decide it won’t hurt to save them for the next time you get sick – save the copay, right?

Except, here’s what you might have learned if everyone hadn’t been too busy to tell you why you have to take the pills the way they tell you. Every day in your body, evolution is pushing bacteria forward to be better, stronger, more fit for survival. The ones that successfully reproduce, that divide to make another copy, to increase the population of bacteria, those are the fittest. They’re the best. You have bacteria that live inside of you, on you, around you, as a part of you. It’s your microbiome, and it’s shaped by everything you do, everything you eat, every move you make, and also by choices your parents made when you were tiny. In fact, there are more cells in and on you that are part of your microbiome than there are cells that are actually you. These cells are responsible for teaching your immune system how to respond to pathogens, they teach our bodies tolerance, they allow digestion of certain foods, and in some cases, the presence of one helps prevent the excess of another. Microbes are your friends.

But you’re sick, and you dislike microbes at the moment. There’s nothing wrong with that – you managed to get hold of a pathogenic microbe, a disease-causing bacteria that was stronger, more fit for survival, than the ones already present inside you. When your immune system met this bacteria, it started fighting. You’ve probably got fever, inflammation, and pain. Depending on where the infection is, you might have some sort of discharge – sinus infections produce nasty mucous, skin infections produce pus, etc. There might even be swelling. All of this is part of your immune system rushing to fight off the microbial invaders. If you weren’t miserable, you’d be dying. That would be worse.

So the doctor, who wisely knew which antibiotic to prescribe because tests determined which bacteria caused the infection, gave your immune system a boost. The antibiotic is chemical warfare. Or, if you dislike that imagery, antibiotics are assistants for immune cells. They come in and target bacteria specifically. In fact, most antibiotics work by targeting things in bacteria that the human (or animal) body lacks.

But we come back to the problem of susceptibility and evolution now. If the doctor writes a prescription for an antibiotic that targets Sal, but the bacteria making you sick is Jim, that antibiotic isn’t going to do much to make you better. If the doctor decides to write a prescription that will kill Sal, Jim, and Sue, then the antibiotic may well make you better, but it also risks making you sick when the balance in your body is thrown off (that’s why there’s a pro-biotics craze, and why, any time I take an antibiotic of any kind, I eat yogurt).

I said the doctor had prescribed the right antibiotic, so it was Sal making you sick, and the antibiotic is for Sal, not Jim. Let’s say you managed to get some bad chicken because a new guy at the local fast food place accidentally cooked the chicken in the fish vat, and it didn’t cook long enough or hot enough to kill the Salmonella inside the chicken, and you got sick (these things happen). Your immune system does what it can, but Sal just overwhelms you. The first antibiotic makes it in, and the sulfa drugs help wipe out everything in their path. But it only takes an hour or two for Sal and his family to reproduce (versus the 10 months that humans are pregnant, and the 11-15 years it takes to reach sexual maturity after birth). So if you ate one piece of chicken at 6 pm with just one bacteria, in 12 hours, there are 4096 bacteria in your system. That might be enough to make you sick. But 12 hours after that, when there are 16 million bacteria in your system, your immune system starts struggling to keep up, and you got sick. So the assistance of the medication is welcome, but it’s fighting millions of bacteria. If you waited 3 days to get to the doctor, Sal had the chance to make over 4 sextillion copies of himself before the antibiotics got on board (that’s a 4 with 21 zeros behind it, or 4,000,000,000,000,000,000,000). That’s starting with one bacteria, doubling every hour, for 72 hours.

OK, so let’s think about this for a minute. Four sextillion copies. The bacteria made a copy of itself every hour. Changes had to creep in. Not all at once, mind you, not big ones. But a copy of a copy of a copy starts to look pretty bad, and once you’ve copied a copy 72 times, even the best copier isn’t going to be perfect. So now there’s copies out there with little changes. Some of them will make absolutely no difference. In fact, odds are good that lots of them will make no difference. The whole process of DNA to RNA to protein is set up to allow for a certain amount of wiggle room, so that when little changes creep in, there’s room. But there’s only a little bit of wiggle room, and there’s been lots of wiggling. So there will have been changes that were bad for Sal’s offspring. Some of the four sextillion new Sals just aren’t as strong as Sal was. The immune system will get to them and take them out, if the immune system can just reach them (that’s a lot of cells. Good thing you have diarrhea. You’re getting rid of a lot of cells).

But in all of those wiggles, some of the wiggles will make some of Sal’s offspring more likely to survive. When the immune system comes looking, these new Sal Jrs have wiggled just enough to be able to hide better, or duck better, or fight better. They live where Sal died. And every hour, when the four sextillion cells divide, those changes get passed on. The weak ones die out, the Sals and Sal equivalents keep going, and the SuperSals keep getting stronger.

That’s when you take the first antibiotic. It takes 20 minutes to hit your system, and it wipes out the weaklings and a fair sized chunk of Sal and his buddies. It may even wipe out some of the SuperSals. Your immune system gets room to work, helps wipe out more weaklings, more Sals, and so on. But every hour, the survivors divide and make more. Your next dose of medicine comes after the Sals have had 8-12 generations to adapt to what you just threw at them. That’s not much, and the meds do a great job of killing off more, but every single time, guess who survives? That’s right – the strongest. The Super-Sals. The ones who know how to survive against the very medicine you’re taking.

Now, if you do what the doctor told you to do, and you take every pill on time, even when you feel better, and you finish your prescription as directed, then the antibiotics help your immune system do what it was struggling to do alone, and your body wipes out the infection, and eventually, may even get around to killing the super-sals. But what if you quit? What if, when you started feeling better, you stopped taking the pills? What happens then?

Oh, you feel better. You gave your immune system room to work, and it did a great job. But you didn’t finish the job. You quit before you were done, and you left the strongest to survive. The only bacteria left alive in your body now are resistant to the drugs you were taking. You quit, thinking you were ahead, but the truth is, you gave them exactly what they needed to take you out, because now, the doctor doesn’t have the tools needed to treat you when you get sick again. And you will – the new generation of SuperSals are going to keep growing and dividing. And every generation will have those wibbly wobbly errors. Yes, some will make them weaker, and even kill them, but most will not. Most will keep them SuperSals. And some will make them even stronger. Because you quit.

Which is why, my dearest friends and families, when you take antibiotics, I will hound you to take every single pill, on time, until the prescription is gone, as directed. Because otherwise, you’ve quit at the deadliest possible time. You’ve handed the bacteria everything they needed to become even more resistant to even more drugs – and to make you sicker still.

What if you do take your antibiotics like you should, but your doctor gives them for the flu? Watch for “No, the Z-Pack won’t treat the Flu”. And for more on antibiotic free meat, look for “SuperChickens?”

Now that I finished my Bachelor’s of Science in Medical/Molecular Biology, I’m working on getting this thing running again. I’m also trying to get another website I had up and running again, and I thought I could combine both. If you check out HuMJah.com, you will hopefully start to find my content appearing there! For now, it’ll be a little at a time, but I’ve set an hour each day aside for writing, and I’ve also made it easy for me to share interesting things when I find them, so let’s see how this goes!

Antibiotics are less than 100 years old. That means there are people alive today who were born when mothers and infants still died of childbed fever, or streptococcal infections. While the risk of infection remains, the use of antibiotics has almost completely eliminated the risk of death due to infection during childbirth.
Likewise, before World War II, soldiers didn’t have to receive a mortal wound to die during war. Injuries and illnesses that we now treat with 5-10 days of antibiotics took the lives of soldiers, nurses, doctors, and civilians. In 1936, the son of president Franklin Delano Roosevelt lay on the edge of death, until an experimental treatment with the first commercially produced antibiotic wiped out the streptococcal infection in his body. Prontosil would earn its discoverer, Gerhard Domagk, a Nobel Prize for Medicine in 1939. Penicillin, the first natural antibiotic (derived from the fungus Penicillium, found growing on a forgotten petri plate in the lab of Alexander Fleming where it inhibited microbial growth), became available in the 1940s.
These miracle drugs helped wipe out the terrible scourges that had plagued mankind for centuries, including combating a disease so prevalent it had multiple names based on which symptoms manifested. Infection with Mycobacterium tuberculosis could cause consumption, or phthisis, as so many knew what we call simply TB. It could also cause terrible inflammation in lymph nodes and produce scrofula, creating a chronic mass in the neck that might eventually form a sinus and then an open wound. The introduction in 1946 of streptomycin, an antibiotic for tuberculosis, gave patients an option that wasn’t isolation or surgery to treat their disease.
Today, however, streptomycin is no longer an option for TB patients. Though you will hear of patients with penicillin allergies, it is rarely, if ever prescribed. Instead, when doctors and pharmacists refer to penicillin allergies, they’re referring to the class of drugs derived from penicillin, drugs which are chemically similar in structure, but not identical. Allergies aren’t the issue, either. Resistance is.
Let’s address what these two mechanisms are so that you can understand the problem before us. Drug allergies occur when the patient taking a medication has an immunological response to the medication. The patient’s body has inappropriately formed antibodies against the drug (or, if the drug is too small, as with haptens, the body has antibodies against the protein produced when the drug binds to its receptor in the body). These antibodies then attack the body whenever the drug is present – no drug, no reaction. Every time the drug is given, the body overreacts, and every time is worse than the time before. The rule of thumb for allergies is simple: The first time is free, but the price you pay escalates every time after.
Resistance, however, occurs within the bacteria, the organisms being targeted by the drug for elimination. All bacteria carry their basic genetic code within them, just like all humans do, and all cows, sheep, dogs, chickens, pigs, ducks, bugs, corn, grass, mushrooms, etc. In that way, we’re all alike. But bacteria have a means of packing extra information inside, little bonuses. These little bonuses are extra pieces of DNA called plasmids, and while they can be packaged in with the rest of the genetic code of the bacteria, they don’t have to be. They can be just tiny little circles of bonus features tucked inside, waiting to be shared.
Plasmids carry things like fertility, which is sort of a misleading term, since bacteria don’t reproduce the way people do. All bacteria are clones – they just copy themselves and then bud off the copy, resulting in two identical cells from one. There’s no need for fertility for that. No, fertility plasmids allow a structure called a pili to be extended from one bacteria to another, and the one who sends the pili can then send a plasmid. Now the second bacterium has a plasmid for fertility, too.
Let’s make this a little easier to see. I’m going to rephrase this as an analogy, a story between Sue, Jim, and Sal. Even though all bacteria reproduce asexually and thus are called mother and daughter cells, we’re going to call our bacteria “Sue” ,“Jim”, and “Sal”.
Sue is a very happy Streptococcus. She’s living life just like all her mother did and her sister and the mothers and sisters before her – synthesize DNA, transcribe DNA into RNA, translate the RNA into amino acids which assemble into peptides and fold into proteins that Sue can use to do everything Sue needs to survive. Good Sue.
Jim’s a peachy keen Escherichia. He has no idea he smells bad (and poor guy, he reeks). He just goes through life, just like Sue, just like his mother and his sisters, synthesizing DNA, transcribing it, translating it, using his proteins…
As Jim happens to be carried past Sue by the current today, Sue’s proteins have made a pili. In and amongst her DNA is a plasmid for pili, and that’s one of the ones she’s expressing. It brushes against Jim, and the two cells connect. As soon as that happens, Streptococcus Sue’s plasmid starts to travel down her pili to Escherichia Jim’s cell. It doesn’t matter that they’re different kinds of cells. She’s got a pili and she’s got a plasmid, and bacteria love to share.
The current didn’t stop, of course, and the connection was always tenuous, so it’s not long at all before the pili breaks loose. Sue goes back to drifting along. She’ll probably make contact with some of Jim’s siblings, and her siblings will probably make contact with Jim – bacteria love to share, and they don’t like to be alone. By the end, Sue’s plasmid has made it not just to Jim but probably to several of his siblings, but we’re going to leave poor Sue behind.
Jim finds his new plasmid and plugs it in. This is nifty stuff. Now he can make a pili, too! He practices. As he’s drifting along in the current, extending his new pili, Jim encounters Sal, the Salmonella (Yeah, yeah, on the nose, whatever). Sal also has a pili, but Sal has a different kind of plasmid to share with his pili plasmid. Sal knows how to fight off sulfa-antibiotics. Bacteria like to share. Sal shares this plasmid, this resistance to sulfa-drugs, with Jim, with all of Jim’s siblings, and now, every bacteria Jim encounters will also gain resistance to sulfa antibiotics. It didn’t matter that Jim and Sal were different kinds of bacteria, or even that Jim didn’t care about Sulfa antibiotics. Jim is a bacteria, and Bacteria Share.
In the 90 years since penicillin was discovered, bacteria have shared resistance to it so extensively that it is largely useless. In the 70 years since streptomycin’s introduction, bacteria have shared resistance to it so extensively that it is largely useless. Bacteria Share. They share with every bacteria, and they do it faster than we can fight them, faster than we can find new drugs, terrifyingly fast. But that’s not why we may lose the single greatest weapon we’ve had in the war on disease in the past century.
If all we were fighting was the fact that Bacteria Share, we could deal with that. The bigger issue comes when you and I help the bacteria. Stay tuned for “SuperChickens?”, “Quitting when you’re not really ahead”, and “No, the Z-Pack won’t treat the Flu”.

This Thursday brings you a variety of information about blood types: First, there’s an article from Wellcome Trust’s Mosaic Science on why we actually have blood types. This is followed by a graphic from Wikimedia that illustrates the carbohydrate attachments that are actually responsible for the different ABO blood types. Finally, a graphic on the levels that the Japanese have taken all of this blood type to (if you don’t already know, the fact that the Japanese are involved should give you a hint…)

Why do we have blood types?

More than a century after their discovery, we still don’t really know what blood types are for. Do they really matter? Carl Zimmer investigates.

When my parents informed me that my blood type was A+, I felt a strange sense of pride. If A+ was the top grade in school, then surely A+ was also the most excellent of blood types – a biological mark of distinction.

It didn’t take long for me to recognise just how silly that feeling was and tamp it down. But I didn’t learn much more about what it really meant to have type A+ blood. By the time I was an adult, all I really knew was that if I should end up in a hospital in need of blood, the doctors there would need to make sure they transfused me with a suitable type.

And yet there remained some nagging questions. Why do 40 per cent of Caucasians have type A blood, while only 27 per cent of Asians do? Where do different blood types come from, and what do they do?;To get some answers, I went to the experts – to haematologists, geneticists, evolutionary biologists, virologists and nutrition scientists.

In 1900 the Austrian physician Karl Landsteiner first discovered blood types, winning the Nobel Prize in Physiology or Medicine for his research in 1930. Since then scientists have developed ever more powerful tools for probing the biology of blood types. They’ve found some intriguing clues about them – tracing their deep ancestry, for example, and detecting influences of blood types on our health. And yet I found that in many ways blood types remain strangely mysterious. Scientists have yet to come up with a good explanation for their very existence.

“Isn’t it amazing?” says Ajit Varki, a biologist at the University of California, San Diego. “Almost a hundred years after the Nobel Prize was awarded for this discovery, we still don’t know exactly what they’re for.”;

My knowledge that I’m type A comes to me thanks to one of the greatest discoveries in the history of medicine. Because doctors are aware of blood types, they can save lives by transfusing blood into patients. But for most of history, the notion of putting blood from one person into another was a feverish dream.

Renaissance doctors mused about what would happen if they put blood into the veins of their patients. Some thought that it could be a treatment for all manner of ailments, even insanity. Finally, in the 1600s, a few doctors tested out the idea, with disastrous results. A French doctor injected calf’s blood into a madman, who promptly started to sweat and vomit and produce urine the colour of chimney soot. After another transfusion the man died.

Such calamities gave transfusions a bad reputation for 150 years. Even in the 19th century only a few doctors dared try out the procedure. One of them was a British physician named James Blundell. Like other physicians of his day, he watched many of his female patients die from bleeding during childbirth. After the death of one patient in 1817, he found he couldn’t resign himself to the way things were.

“I could not forbear considering, that the patient might very probably have been saved by transfusion,” he later wrote.

Blundell became convinced that the earlier disasters with blood transfusions had come about thanks to one fundamental error: transfusing “the blood of the brute”, as he put it. Doctors shouldn’t transfer blood between species, he concluded, because “the different kinds of blood differ very importantly from each other”.

Human patients should only get human blood, Blundell decided. But no one had ever tried to perform such a transfusion. Blundell set about doing so by designing a system of funnels and syringes and tubes that could channel blood from a donor to an ailing patient. After testing the apparatus out on dogs, Blundell was summoned to the bed of a man who was bleeding to death. “Transfusion alone could give him a chance of life,” he wrote.

Several donors provided Blundell with 14 ounces of blood, which he injected into the man’s arm. After the procedure the patient told Blundell that he felt better – “less fainty” – but two days later he died.

Still, the experience convinced Blundell that blood transfusion would be a huge benefit to mankind, and he continued to pour blood into desperate patients in the following years. All told, he performed ten blood transfusions. Only four patients survived.

While some other doctors experimented with blood transfusion as well, their success rates were also dismal. Various approaches were tried, including attempts in the 1870s to use milk in transfusions (which were, unsurprisingly, fruitless and dangerous).

Blundell was correct in believing that humans should only get human blood. But he didn’t know another crucial fact about blood: that humans should only get blood from certain other humans. It’s likely that Blundell’s ignorance of this simple fact led to the death of some of his patients. What makes those deaths all the more tragic is that the discovery of blood types, a few decades later, was the result of a fairly simple procedure.

The first clues as to why the transfusions of the early 19th century had failed were clumps of blood. When scientists in the late 1800s mixed blood from different people in test tubes, they noticed that sometimes the red blood cells stuck together. But because the blood generally came from sick patients, scientists dismissed the clumping as some sort of pathology not worth investigating. Nobody bothered to see if the blood of healthy people clumped, until Karl Landsteiner wondered what would happen. Immediately, he could see that mixtures of healthy blood sometimes clumped too.

Landsteiner set out to map the clumping pattern, collecting blood from members of his lab, including himself. He separated each sample into red blood cells and plasma, and then he combined plasma from one person with cells from another.

Landsteiner found that the clumping occurred only if he mixed certain people’s blood together. By working through all the combinations, he sorted his subjects into three groups. He gave them the entirely arbitrary names of A, B and C. (Later on C was renamed O, and a few years later other researchers discovered the AB group. By the middle of the 20th century the American researcher Philip Levine had discovered another way to categorise blood, based on whether it had the Rh blood factor. A plus or minus sign at the end of Landsteiner’s letters indicates whether a person has the factor or not.)

When Landsteiner mixed the blood from different people together, he discovered it followed certain rules. If he mixed the plasma from group A with red blood cells from someone else in group A, the plasma and cells remained a liquid. The same rule applied to the plasma and red blood cells from group B. But if Landsteiner mixed plasma from group A with red blood cells from B, the cells clumped (and vice versa).

The blood from people in group O was different. When Landsteiner mixed either A or B red blood cells with O plasma, the cells clumped. But he could add A or B plasma to O red blood cells without any clumping.

It’s this clumping that makes blood transfusions so potentially dangerous. If a doctor accidentally injected type B blood into my arm, my body would become loaded with tiny clots. They would disrupt my circulation and cause me to start bleeding massively, struggle for breath and potentially die. But if I received either type A or type O blood, I would be fine.

Landsteiner didn’t know what precisely distinguished one blood type from another. Later generations of scientists discovered that the red blood cells in each type are decorated with different molecules on their surface. In my type A blood, for example, the cells build these molecules in two stages, like two floors of a house. The first floor is called an H antigen. On top of the first floor the cells build a second, called the A antigen.

People with type B blood, on the other hand, build the second floor of the house in a different shape. And people with type O build a single-storey ranch house: they only build the H antigen and go no further.

Each person’s immune system becomes familiar with his or her own blood type. If people receive a transfusion of the wrong type of blood, however, their immune system responds with a furious attack, as if the blood were an invader. The exception to this rule is type O blood. It only has H antigens, which are present in the other blood types too. To a person with type A or type B, it seems familiar. That familiarity makes people with type O blood universal donors, and their blood especially valuable to blood centres.

Landsteiner reported his experiment in a short, terse paper in 1900. “It might be mentioned that the reported observations may assist in the explanation of various consequences of therapeutic blood transfusions,” he concluded with exquisite understatement. Landsteiner’s discovery opened the way to safe, large-scale blood transfusions, and even today blood banks use his basic method of clumping blood cells as a quick, reliable test for blood types.

But as Landsteiner answered an old question, he raised new ones. What, if anything, were blood types for? Why should red blood cells bother with building their molecular houses? And why do people have different houses?

Solid scientific answers to these questions have been hard to come by. And in the meantime, some unscientific explanations have gained huge popularity. “It’s just been ridiculous,” sighs Connie Westhoff, the Director of Immunohematology, Genomics, and Rare Blood at the New York Blood Center.;

In 1996 a naturopath named Peter D’Adamo published a book called Eat Right 4 Your Type. D’Adamo argued that we must eat according to our blood type, in order to harmonise with our evolutionary heritage.

Blood types, he claimed, “appear to have arrived at critical junctures of human development.” According to D’Adamo, type O blood arose in our hunter-gatherer ancestors in Africa, type A at the dawn of agriculture, and type B developed between 10,000 and 15,000 years ago in the Himalayan highlands. Type AB, he argued, is a modern blending of A and B.

From these suppositions D’Adamo then claimed that our blood type determines what food we should eat. With my agriculture-based type A blood, for example, I should be a vegetarian. People with the ancient hunter type O should have a meat-rich diet and avoid grains and dairy. According to the book, foods that aren’t suited to our blood type contain antigens that can cause all sorts of illness. D’Adamo recommended his diet as a way to reduce infections, lose weight, fight cancer and diabetes, and slow the ageing process.

D’Adamo’s book has sold 7 million copies and has been translated into 60 languages. It’s been followed by a string of other blood type diet books; D’Adamo also sells a line of blood-type-tailored diet supplements on his website. As a result, doctors often get asked by their patients if blood type diets actually work.

The best way to answer that question is to run an experiment. In Eat Right 4 Your Type D’Adamo wrote that he was in the eighth year of a decade-long trial of blood type diets on women with cancer. Eighteen years later, however, the data from this trial have not yet been published.

Recently, researchers at the Red Cross in Belgium decided to see if there was any other evidence in the diet’s favour. They hunted through the scientific literature for experiments that measured the benefits of diets based on blood types. Although they examined over 1,000 studies, their efforts were futile. “There is no direct evidence supporting the health effects of the ABO blood type diet,” says Emmy De Buck of the Belgian Red Cross-Flanders.

After De Buck and her colleagues published their review in the American Journal of Clinical Nutrition, D’Adamo responded on his blog. In spite of the lack of published evidence supporting his Blood Type Diet, he claimed that the science behind it is right. “There is good science behind the blood type diets, just like there was good science behind Einstein’s mathmatical [sic] calculations that led to the Theory of Relativity,” he wrote.

Comparisons to Einstein notwithstanding, the scientists who actually do research on blood types categorically reject such a claim. “The promotion of these diets is wrong,” a group of researchers flatly declared in Transfusion Medicine Reviews.

Nevertheless, some people who follow the Blood Type Diet see positive results. According to Ahmed El-Sohemy, a nutritional scientist at the University of Toronto, that’s no reason to think that blood types have anything to do with the diet’s success.

El-Sohemy is an expert in the emerging field of nutrigenomics. He and his colleagues have brought together 1,500 volunteers to study, tracking the foods they eat and their health. They are analysing the DNA of their subjects to see how their genes may influence how food affects them. Two people may respond very differently to the same diet based on their genes.

“Almost every time I give talks about this, someone at the end asks me, ‘Oh, is this like the Blood Type Diet?’” says El-Sohemy. As a scientist, he found Eat Right 4 Your Type lacking. “None of the stuff in the book is backed by science,” he says. But El-Sohemy realised that since he knew the blood types of his 1,500 volunteers, he could see if the Blood Type Diet actually did people any good.

El-Sohemy and his colleagues divided up their subjects by their diets. Some ate the meat-based diets D’Adamo recommended for type O, some ate a mostly vegetarian diet as recommended for type A, and so on. The scientists gave each person in the study a score for how well they adhered to each blood type diet.

The researchers did find, in fact, that some of the diets could do people some good. People who stuck to the type A diet, for example, had lower body mass index scores, smaller waists and lower blood pressure. People on the type O diet had lower triglycerides. The type B diet – rich in dairy products – provided no benefits.

“The catch,” says El-Sohemy, “is that it has nothing to do with people’s blood type.” In other words, if you have type O blood, you can still benefit from a so-called type A diet just as much as someone with type A blood – probably because the benefits of a mostly vegetarian diet can be enjoyed by anyone. Anyone on a type O diet cuts out lots of carbohydrates, with the attending benefits of this being available to virtually everyone. Likewise, a diet rich in dairy products isn’t healthy for anyone – no matter their blood type.

One of the appeals of the Blood Type Diet is its story of the origins of how we got our different blood types. But that story bears little resemblance to the evidence that scientists have gathered about their evolution.

After Landsteiner’s discovery of human blood types in 1900, other scientists wondered if the blood of other animals came in different types too. It turned out that some primate species had blood that mixed nicely with certain human blood types. But for a long time it was hard to know what to make of the findings. The fact that a monkey’s blood doesn’t clump with my type A blood doesn’t necessarily mean that the monkey inherited the same type A gene that I carry from a common ancestor we share. Type A blood might have evolved more than once.

The uncertainty slowly began to dissolve, starting in the 1990s with scientists deciphering the molecular biology of blood types. They found that a single gene, called ABO, is responsible for building the second floor of the blood type house. The A version of the gene differs by a few key mutations from B. People with type O blood have mutations in the ABO gene that prevent them from making the enzyme that builds either the A or B antigen.

Scientists could then begin comparing the ABO gene from humans to other species. Laure Ségurel and her colleagues at the National Center for Scientific Research in Paris have led the most ambitious survey of ABO genes in primates to date. And they’ve found that our blood types are profoundly old. Gibbons and humans both have variants for both A and B blood types, and those variants come from a common ancestor that lived 20 million years ago.

Our blood types might be even older, but it’s hard to know how old. Scientists have yet to analyse the genes of all primates, so they can’t see how widespread our own versions are among other species. But the evidence that scientists have gathered so far already reveals a turbulent history to blood types. In some lineages mutations have shut down one blood type or another. Chimpanzees, our closest living relatives, have only type A and type O blood. Gorillas, on the other hand, have only B. In some cases mutations have altered the ABO gene, turning type A blood into type B. And even in humans, scientists are finding, mutations have repeatedly arisen that prevent the ABO protein from building a second storey on the blood type house. These mutations have turned blood types from A or B to O. “There are hundreds of ways of being type O,” says Westhoff.

Being type A is not a legacy of my proto-farmer ancestors, in other words. It’s a legacy of my monkey-like ancestors. Surely, if my blood type has endured for millions of years, it must be providing me with some obvious biological benefit. Otherwise, why do my blood cells bother building such complicated molecular structures?

Yet scientists have struggled to identify what benefit the ABO gene provides. “There is no good and definite explanation for ABO,” says Antoine Blancher of the University of Toulouse, “although many answers have been given.”

The most striking demonstration of our ignorance about the benefit of blood types came to light in Bombay in 1952. Doctors discovered that a handful of patients had no ABO blood type at all – not A, not B, not AB, not O. If A and B are two-storey buildings, and O is a one-storey ranch house, then these Bombay patients had only an empty lot.

Since its discovery this condition – called the Bombay phenotype – has turned up in other people, although it remains exceedingly rare. And as far as scientists can tell, there’s no harm that comes from it. The only known medical risk it presents comes when it’s time for a blood transfusion. Those with the Bombay phenotype can only accept blood from other people with the same condition. Even blood type O, supposedly the universal blood type, can kill them.

The Bombay phenotype proves that there’s no immediate life-or-death advantage to having ABO blood types. Some scientists think that the explanation for blood types may lie in their variation. That’s because different blood types may protect us from different diseases.

Doctors first began to notice a link between blood types and different diseases in the middle of the 20th century, and the list has continued to grow. “There are still many associations being found between blood groups and infections, cancers and a range of diseases,” Pamela Greenwell of the University of Westminster tells me.

From Greenwell I learn to my displeasure that blood type A puts me at a higher risk of several types of cancer, such as some forms of pancreatic cancer and leukaemia. I’m also more prone to smallpox infections, heart disease and severe malaria. On the other hand, people with other blood types have to face increased risks of other disorders. People with type O, for example, are more likely to get ulcers and ruptured Achilles tendons.

These links between blood types and diseases have a mysterious arbitrariness about them, and scientists have only begun to work out the reasons behind some of them. For example, Kevin Kain of the University of Toronto and his colleagues have been investigating why people with type O are better protected against severe malaria than people with other blood types. His studies indicate that immune cells have an easier job of recognising infected blood cells if they’re type O rather than other blood types.

More puzzling are the links between blood types and diseases that have nothing to do with the blood. Take norovirus. This nasty pathogen is the bane of cruise ships, as it can rage through hundreds of passengers, causing violent vomiting and diarrhoea. It does so by invading cells lining the intestines, leaving blood cells untouched. Nevertheless, people’s blood type influences the risk that they will be infected by a particular strain of norovirus.

The solution to this particular mystery can be found in the fact that blood cells are not the only cells to produce blood type antigens. They are also produced by cells in blood vessel walls, the airway, skin and hair. Many people even secrete blood type antigens in their saliva. Noroviruses make us sick by grabbing onto the blood type antigens produced by cells in the gut.

Yet a norovirus can only grab firmly onto a cell if its proteins fit snugly onto the cell’s blood type antigen. So it’s possible that each strain of norovirus has proteins that are adapted to attach tightly to certain blood type antigens, but not others. That would explain why our blood type can influence which norovirus strains can make us sick.

It may also be a clue as to why a variety of blood types have endured for millions of years. Our primate ancestors were locked in a never-ending cage match with countless pathogens, including viruses, bacteria and other enemies. Some of those pathogens may have adapted to exploit different kinds of blood type antigens. The pathogens that were best suited to the most common blood type would have fared best, because they had the most hosts to infect. But, gradually, they may have destroyed that advantage by killing off their hosts. Meanwhile, primates with rarer blood types would have thrived, thanks to their protection against some of their enemies.

As I contemplate this possibility, my type A blood remains as puzzling to me as when I was a boy. But it’s a deeper state of puzzlement that brings me some pleasure. I realise that the reason for my blood type may, ultimately, have nothing to do with blood at all.

All red blood cells have a specific chain of carbohydrates, and then the presence or absence of specific carbohydrates at the distal terminal of the chain determines the blood type. There are 4 phenotypes in blood types, but that is determined by 6 genotypes. In other words, your mother gave you one set of genes, your father gave you another, and these combine to form your genotype which is expressed as a specific physical expression known as a phenotype. (If you’ve read the article, most of this should be review).

So, you can be AA, AO, BB, BO, AB, or OO: these are the 6 genotypes. AA and AO would both be expressed as type A blood, just as BB and BO would both be expressed as type B blood, which is how 6 genotypes distill into 4 phenotypes. But how does this tie back to the carbohydrates? Well, all cells have tags on them that identify them as you. These tags are proteins embedded in the lipid membranes of your cell with carbohydrates attached at the end. In the case of blood types, as I mentioned, all four blood types start with the same chain, varying only at the distal terminal. Add a galactose sugar on to your chain, and you have a B-type tag. Take that same galactose, swap out an amino for one of the carbons and attach an acetyl group and you get N-acetylgalactosamine – and now that’s an A-type tag. Omit either sugar – galactose or the souped up version – and you have the O-type tag. Now, on your cells, you’re going to have tags show up in pairs: you can have A-type tags, B-type tags, or O-type tags. If you have all O-type tags, you have type O blood. If you have any A-type tags but NO B-type tags, you’ve got type A, whether that’s all type A (AA) or only half type A (AO). If you’ve got B but not A, you’ve got B blood (BB, or BO). It’s when you get cells that have both the type A tag (N-acetylgalactosamine) AND the type B tag (galactose) that you get type AB blood. That’s what this image is showing. I wanted to be sure to illustrate the biochemistry of this clearly.

A story started circulating last week focusing on zinc finger nucleases. These are enzymes that cut DNA in a very specific way, allowing for a new, different means of altering genes in vitro and possibly in vivo. Genetic treatments are the exciting future medicine we all hope for, especially with the genetic disorders that are inborn and uncorrectable otherwise. The ability to correct disorders by correcting the body at the genes is exciting, so this story generates lots of interest. Read it yourself here.